CISPLATIN COMBINED WITH THE NEW CISPLATIN-PROCAINE COMPLEX DPR - IN-VITRO AND IN-VIVO STUDIES

The administration of combinations of platinum compounds is considered as a useful alternative therapeutic strategy to avoid the complicatio ns of toxic events during cancer chemotherapy in order to obtain a the rapeutic advantage. On the basis of previous in vitro and in vivo find ings, suggesting an antitumour activity of the new cisplatin-derived c ompound cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N- 4]-chlorideplatinum(II) monohydrochloride monohydrate (DPR), we invest igated the effectiveness of the combination of cisplatin (DDP) and DPR in vitro on murine leukaemic cells, which were either sensitive (P388 ) or resistant (L1210/DDP) to DDP, and on the murine M5076 reticulum c ell sarcoma, and in vivo in BDF1 female mice transplanted with P388 le ukaemic cells or cisplatin-resistant L1210/DDP leukaemic cells. The co ntemporaneous exposure in vitro to both platinum compounds gave a sign ificantly higher cell growth inhibition than that expected on the basi s of dose-response curves for single agents in all tumour models teste d. In vivo, the combinations of DDP plus DPR elicited significant enha ncement over the activity of the drugs alone both in the ascitic and s olid P388 models. The combined treatment of 10 mg/kg DDP and 14 mg/kg DPR yielded 62.5% tumour-free mice compared with 6.2% with 10 mg/kg DD P alone, the best single agent. It is noteworthy that the combined app lication of DDP and DPR was also very effective in the solid cisplatin -resistant L1210/DDP model, inducing a significant reduction in the vo lume of tumour. A therapeutic advantage was achieved with combination treatments that had no effect on platinum-mediated body weight loss an d were generally well tolerated by the mice. At equitoxic concentratio ns of DPR and carboplatin, the treatment with DDP plus DPR proved to h ave a higher efficacy against this tumour model compared to that obser ved after the combined treatment with DDP and carboplatin. In summary, the combination of DDP and DPR showed a therapeutic advantage over si ngle drug treatment and has demonstrated promise at the preclinical le vel in its ability to circumvent acquired resistance to DDP both in vi tro and in vivo. Copyright (C) 1996 Elsevier Science Ltd